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Abstract

Background

This case report highlights the relevance of quantifying the BCR-ABL gene in cerebrospinal
fluid of patients with suspected relapse of chronic myeloid leukemia in the central
nervous system.

Case presentation

We report on a female patient with isolated central nervous system relapse of chronic
myeloid leukemia (CML) during peripheral remission after allogeneic hematopoietic
stem cell transplantation. The patient showed a progressive cognitive decline as the
main symptom. MRI revealed a hydrocephalus and an increase in cell count in the cerebrospinal
fluid (CSF) with around 50% immature blasts in the differential count. A highly elevated
BCR-ABL/ ABL ratio was detected in the CSF, whilst the ratio for peripheral blood
and bone marrow was not altered. On treatment of the malresorptive hydrocephalus with
shunt surgery, the patient showed an initial cognitive improvement, followed by a
secondary deterioration. At this time, the cranial MRI showed leukemic infiltration
of lateral ventricles walls. Hence, intrathecal administration of cytarabine, methotrexate,
and dexamethasone was initiated, which caused a significant decrease of cells in the
CSF. Soon after, the patient demonstrated significant cognitive improvement with a
good participation in daily activities. At a later time point, after the patient had
lost the major molecular response of CML, therapy with dasatinib was initiated. In
a further follow-up, the patient was neurologically and hematologically stable.

Conclusions

In patients with treated CML, the rare case of an isolated CNS blast crisis has to
be taken into account if neurological symptoms evolve. The analysis of BCR-ABL in
the CSF is a further option for the reliable detection of primary isolated relapse
of CML in these patients.

Keywords:

Chronic myeloid leukemia; CNS relapse; BCR-ABL

Background

Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the
presence of the Philadelphia chromosome which is caused by a reciprocal translocation
between chromosome 9 and 22. The result is a fusion gene from a part of the BCR (breakpoint cluster region) gene from chromosome 22 and the Abl1 gene from chromosome 9 [1]. Further, extramedullary blast crisis is a known complication of CML. However, the
central nervous system as an isolated site of extramedullary blast crisis is rare
[2].

We report on a 64 year-old woman with CML in remission who developed an isolated central
nervous system relapse after an unrelated one antigen mismatched allogeneic hematopoietic
stem cell transplantation.

Case presentation

CML was first diagnosed in January 2005 with a blast crisis. The patient was subsequently
treated with imatinib. In November 2005, therapy was changed to cytosine arabinoside
and mitoxantrone followed by hydroyurea due to a second blast crisis. Since February
2006, the second generation tyrosine-kinase inhibitor (TKI) dasatinib induced a hematological
remission (chronic phase) until a one antigen mismatched (C-allele locus) unrelated
allogeneic hematopoietic stem cell transplantation (SCT) was performed in May 2006.
After SCT, she developed a series of epileptic seizures owing to posterior reversible
encephalopathy syndrome (PRES) and developed severe critical illness polyneuropathy.
At this time point, the analysis of the CSF was normal (1 cell/μl, total protein 355 mg/l)
pointing neither to inflammation nor to a relapse. After initial severe tetraplegia,
she reconstituted during intensive rehabilitation therapy and could use her arms independently,
but did not regain her ability to walk. Up to November 2007, the patient received
immunosuppressive therapy with ciclosporine and low dose prednisolone was administered
until May 2008 because of a mild hepatic graft-versus-host disease. Cognition remained
unimpaired. In all follow-up hematological visits after transplant, CML was regarded
to be in remission (major cytogenetic and major molecular).

In November 2008, a progressive cognitive decline within a period of 6 months was
noticed which led to a neurological consultation. The patient was mutistic and apathetic
showing psychomotorical impairment and pathologically inadequate laughter. Moreover,
orientation regarding time and place was impaired, but spastic tetraplegia was unchanged.
MRI revealed a hydrocephalus with signs of high brain pressure (Figure 1 A-C). A lumbar puncture showed an elevated total cell count (389 cells /μl) and total
protein (1154 mg/l) with an increased pressure of 26.5 cm H2O. Thus, 30 ml of CSF was drained leading to a significant cognitive improvement.

CSF microbiology excluded an infectious cause of the pleocytosis. In the differential
count of CSF, about 50% immature blasts were counted and 65% myeloid precursor cells
(CD7/CD33 double positive) were detected by FACS-analysis. However, the peripheral
blood differential count was normal and did not point to a systemic hematological
relapse of CML. The BCR-ABL/ ABL ratio (real time PCR) in CSF was 61.44% (and 0.0025%
in the bone marrow).

The malresorptive hydrocephalus was at first treated with shunt surgery since the
hydrocephalus was thought to be the major pathophysiologic factor causing cognitive
decline in the patient. Following surgery, the CSF cell count fell to 66 cells/μl.
However, after initial cognitive improvement, the patient showed a secondary deterioration.
At this time point, leukemic infiltration in the lateral ventricles walls was detected
by cranial MRI (Figure 1 D-F). Total cell and total protein counts were 1024 cells/μl and 2923 mg/l, respectively,
and 66% of the cells were CD7/CD33 double positive by FACS-analysis. In the CSF, differential
count megakaryocytes, immature eosinophils and blast cells were noted. (Figure 1 G). The BCR-ABL/ABL ratio (real time PCR) in the bone marrow had increased from 0.0025%
in the previous analysis to 0.07%.

Triple intrathecal therapy consisting of cytarabine (40 mg), methotrexate (10 mg),
and dexamethasone (4 mg) was initiated, as described in the literature for cases of
CNS relapse [2-4]. Intrathecal chemotherapy was administered twice and caused a significant decrease
of total cell count and protein in the CSF (11 cells/μl, 1254 mg/l protein). Myeloid
precursor cells were reduced to 19% by FACS-analysis. During follow-up examinations,
cognition of the patient was much improved and she showed good participation in daily
activities.

Therapy with dasatinib was begun after initial intrathecal chemotherapy, due to its
ability to cross the blood–brain barrier [5] and because the major molecular response was lost in the consecutive bone marrow
aspiration in February 2009 (BCR-ABL/ ABL ratio (real time PCR): 0.24%). Since then,
the patient has remained neurologically stable with subjective improvement of her
impaired daily activities. No hematological relapse occurred during further patient
follow up and continuous dasatinib therapy. However, the patient was diagnosed with
advanced vulva carcinoma in May 2011 and died in December of the same year.

Discussion

BCR-ABL transcripts are regarded as early markers for a hematological relapse of CML
[1]. Oral tyrosine kinase inhibitors such as imatinib inhibit BCR-ABL-tyrosine kinase.
However, imatinib does not penetrate the blood–brain-barrier so that isolated CNS
blast crises have been described in several cases [2-4]. Single cases of isolated CNS blast crises have also been depicted, for example,
in one patient under dasatinib [6], a second generation TKI with an improved penetration of the blood–brain-barrier,
and after allogeneic hematopoietic stem cell transplantation in two cases [7]. Thus, the CNS has to be regarded as a sanctuary site of relapse. This may generally
be caused by decreased levels of the drugs being found in the CNS [2]. The history of CNS involvement before hematopoietic stem cell transplantation has
been identified as significant predictors for CNS relapse after hematopoietic stem
cell transplantation [7].

The isolated CNS relapse in our patient was detected due to the presence of blasts
and other myeloid precursor cells in the CSF as well as increased BCR-ABL quantities
over time, while blood and bone marrow did not reveal such abnormalities at that time.
The increase of cells in CNS led to a malresorptive hydrocephalus which had to be
treated with shunt surgery. The treatment of isolated CNS relapse comprises of intrathecal
chemotherapy and/or cranial irradiation [7]. Donor lymphocyte infusion (DLI) was not considered as the first therapeutic option
in this case, due to the dramatical clinical course. Intrathecal chemotherapy led
to a significant reduction of CSF cells indicating successful control of CNS disease
besides the neurological improvement, so that additional radiotherapy was not considered.

Conclusion

In patients with treated CML, the rare case of an isolated CNS blast crisis has to
be taken into account if neurological symptoms evolve. Lumbar puncture is obligatory
and isolated CNS relapse of leukaemia can be controlled. The analysis of BCR-ABL in
the CSF is a further option either for reliable detection of isolated relapse or as
the first sign of a consecutive hematological relapse of CML.

Consent

Written informed consent was obtained from the patient for publication of this case
report and accompanying images. A copy of the written consent is available for review
by the Editor in Chief of this journal.

Abbreviations

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

MF and HA drafted the first manuscript and made a contribution to acquisition and
interpretation of data. MF, OW and HA are treating neurologists of the patient and
made a contribution to acquisition and interpretation of data. HGS and AH are treating
hematologists of the patient and had a role in data acquisition and interpretation.
MR and KB performed the laboratory analyses and contributed to acquisition and interpretation
of data. ARS is neuroradiologist and performed and analyzed the MRI data. All authors
revised the manuscript and approved the final manuscript. We thank Nasim Kroegel for
her help in language editing.